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MetroNIDAZOLE (Systemic)

Medically reviewed on September 10, 2018

Pronunciation

(met roe NYE da zole)

Index Terms

  • Benzoyl Metronidazole
  • Flagyl
  • Metronidazole Benzoate
  • Metronidazole Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Flagyl: 375 mg

Generic: 375 mg

Solution, Intravenous:

Generic: 500 mg (100 mL); 5 mg/mL (100 mL)

Tablet, Oral:

Flagyl: 250 mg, 500 mg

Generic: 250 mg, 500 mg

Tablet Extended Release 24 Hour, Oral:

Flagyl ER: 750 mg [DSC]

Brand Names: U.S.

  • Flagyl
  • Flagyl ER [DSC]

Pharmacologic Category

  • Amebicide
  • Antibiotic, Miscellaneous
  • Antiprotozoal, Nitroimidazole

Pharmacology

After diffusing into the organism, interacts with DNA to cause a loss of helical DNA structure and strand breakage resulting in inhibition of protein synthesis and cell death in susceptible organisms

Absorption

Oral: Well absorbed

Distribution

To bile, seminal fluid, bone, liver, and liver abscesses, lung and vaginal secretions; crosses blood-brain barrier; saliva and CSF concentrations similar to those in plasma

Metabolism

Hepatic (30% to 60%) to several metabolites including an active hydroxyl metabolite which maintains activity ~30% to 65% of the parent compound (Lamp 1999)

Excretion

Urine (unchanged drug and metabolites: 60% to 80%; ~20% of total as unchanged drug); feces (6% to 15%)

Time to Peak

Serum: Oral: Immediate release: 1 to 2 hours; Extended release: ~5 hours

Half-Life Elimination

Neonates <7 days (Jager-Roman 1982): Within first week of life, more prolonged than with lower GA:

GA 28 to 30 weeks: 75.3 ± 16.9 hours

GA 32 to 35 weeks: 35.4 ± 1.5 hours

GA 36 to 40 weeks: 24.8 ± 1.6 hours

Neonates ≥7 days: ~22.5 hours (Upadhyaya 1988)

Children and Adolescents: 6 to 10 hours (Lamp 1999)

Adults: ~8 hours

Protein Binding

<20%

Special Populations: Renal Function Impairment

CrCl ≤65 mL/minute: Half-life: 18 to 32 hours (hydroxy metabolite [active]) (Lamp 1999)

Special Populations: Hepatic Function Impairment

Half-life: 18.31 hours (mean) in one study (Lau, 1987)

According to Child-Pugh classification (Muscara, 1995):

Child-Pugh class A: ~10.7 hours

Child-Pugh class B: ~13.5 hours

Child-Pugh class C: ~21.5 hours

Use: Labeled Indications

Amebiasis: Oral immediate-release tablet and capsule: Treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess

Limitations of use: When used for amebic liver abscess, may be used concurrently with percutaneous needle aspiration when it is clinically indicated.

Anaerobic bacterial infections (caused by Bacteroides spp., including the B. fragilis group): Oral immediate-release tablet, capsule, and injection:

Bacterial septicemia: Treatment of bacterial septicemia (also caused by Clostridium spp.)

Bone and joint infections: Treatment (adjunctive therapy) of bone and joint infections

CNS Infections: Treatment of CNS infections, including meningitis and brain abscess

Endocarditis: Treatment of endocarditis

Gynecologic infections: Treatment of gynecologic infections including endometritis, endomyometritis, tubo-ovarian abscess, or postsurgical vaginal cuff infection (also caused by Clostridium spp., Peptococcus spp., Peptostreptococcus spp., and Fusobacterium spp.)

Intra-abdominal infections: Treatment of intra-abdominal infections, including peritonitis, intra-abdominal abscess and liver abscess (also caused by Clostridium spp., Eubacterium spp., Peptococcus spp., and Peptostreptococcus spp.)

Lower respiratory tract infections: Treatment of lower respiratory tract infections, including pneumonia, empyema and lung abscess

Skin and skin structure infections: Treatment of skin and skin structure infections (also caused by Clostridium spp., Peptococcus spp., Peptostreptococcus spp., and Fusobacterium spp.)

Bacterial vaginosis: Oral extended-release tablet: Treatment of bacterial vaginosis in nonpregnant women

Surgical prophylaxis (colorectal surgery): Injection: Preoperative, intraoperative, and postoperative prophylaxis to reduce the incidence of postoperative infection in patients undergoing elective colorectal surgery classified as contaminated or potentially contaminated

Trichomoniasis: Oral immediate-release tablet, capsule: Treatment of infections caused by Trichomonas vaginalis, including treatment of asymptomatic sexual partners

Off Label Uses

Balantidiasis (adults)

Balantidiasis is a worldwide subtropic and tropic parasitic disease due to close contact with swine [Schuster 2008]. Data from a limited number of patients treated with metronidazole (single case report of one immunocompromised patient with pulmonary infection) suggest that metronidazole may be beneficial for the treatment of this condition [Anagyrou 2003]. Additional data may be necessary to further define the role of metronidazole for the treatment of balantidiasis.

Balantidiasis (children/adolescents)

Balantidiasis is a worldwide subtropic and tropic parasitic disease due to close contact with swine [Schuster 2008]. Based on the American Academy of Pediatrics Report of the Committee on Infectious Disease, metronidazole is an effective and recommended alternative treatment for children and adolescents with balantidiasis [AAP [Red Book 2012]].

Bite wounds (animal/human)

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), metronidazole, in combination with a second- or third-generation cephalosporin, levofloxacin, or sulfamethoxazole/trimethoprim for animal bites, or in combination with ciprofloxacin or levofloxacin for human bites, is an effective and recommended alternative for treatment of bite wounds.

Clostridium difficile infection

Based on the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) guidelines for Clostridium difficile infection in adults and children, oral metronidazole is an effective and recommended alternative agent for the management of initial episodes of non-severe (WBC ≤15,000 cells/mm3 and serum creatinine <1.5 mg/dL) C. difficile infections if access to vancomycin or fidaxomicin is limited or use is contraindicated. IV metronidazole is recommended in combination with oral and/or rectal vancomycin for fulminant C. difficile infections, particularly when ileus is present. Metronidazole should not be used for prolonged therapy because of the potential for cumulative and potentially irreversible neurotoxicity; oral metronidazole should not be used for recurrent infections.

Crohn disease (management after surgical resection)

Data from a small double-blind, randomized, placebo-controlled trial supports the use of metronidazole as management of Crohn disease after surgical resection and has demonstrated to lower endoscopic and decreased early clinical recurrence rates [Rutgeerts 1995]. Data from 2 randomized, placebo-controlled trials and a meta-analysis suggest that metronidazole alone is of modest benefit in reduction of postoperative recurrence, whereas metronidazole combined with a thiopurine (eg, azathioprine, mercaptopurine) or anti-tumor necrosing factor (eg, adalimumab) is moderately effective in reducing recurrence rates [De Cruz 2015], [D’Haens 2008], [Peyrin-Biroulet 2009].

Based on the American Gastroenterological Association Institute Guidelines for the Management of Crohn’s Disease after Surgical Resection, metronidazole is a suggested second-line alternative for patients who are concerned about the adverse effects of first-line agent therapy (eg, anti-tumor necrosing factors, thiopurines) and who have a lower risk of recurrence. The American College of Gastroenterology Clinical guideline for management of Crohn Disease in Adults also suggests that metronidazole may be used following small intestine resection in patients with Crohn disease to prevent recurrence [ACG [Lichtenstein 2018]].

Crohn disease, mild to moderate (treatment)

Data from a randomized, controlled trial suggest that metronidazole, in combination with ciprofloxacin, may be beneficial for the treatment of patients with colonic Crohn disease. Additional data may be necessary to further define the role of metronidazole in this condition [Steinhart 2002].

Based on the American College of Gastroenterology practice guidelines for the management of Crohn disease in adults, metronidazole is a suggested alternative agent in the management of mild to moderate Crohn disease not responding to sulfasalazine and in patients with colonic involvement (ileocolitis and colitis).

Dientamoeba fragilis (adults)

Based on the Centers for Disease Control and Prevention (CDC) Resources for Health Professionals, metronidazole is an effective and recommended agent for the treatment of this condition.

Giardiasis

In a meta-analysis of trials evaluating the treatment of giardiasis, the use of metronidazole was found to be of similar effectiveness to albendazole for the treatment of this condition although metronidazole may have slightly more adverse effects [Granados 2012].

Based on the American Academy of Pediatrics Report of the Committee on Infectious Disease, metronidazole is an effective and recommended drug of choice for the treatment of children and adolescents with giardiasis [AAP [Red Book 2012]].

Helicobacter pylori eradication

Based on the American College of Gastroenterology Guideline on the Treatment of Helicobacter pylori Infection and the ESPGHAN/NASPGHAN Guidelines for Helicobacter pylori Infection in Children, metronidazole is an effective and recommended component of a multiple-drug regimen for the treatment of H. pylori infection.

Periodontitis

Data from a randomized, 12 month double-blind placebo controlled trial, though small, evaluating the use of either amoxicillin and metronidazole or placebo in conjunction with aggressive dental care demonstrated that amoxicillin (in combination with metronidazole) significantly improved dental parameters and increased beneficial bacteria [Silva-Senem 2013]. Additional trials may be necessary to further define the role of metronidazole for the treatment of periodontitis.

Pouchitis (acute)

In a systematic review of available clinical trials evaluating the treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis, metronidazole was found to be less effective than ciprofloxacin but as effective as budesonide enemas for inducing remission in acute pouchitis. Metronidazole is considered an effective treatment and as a first line agent for the treatment of this condition [Holubar 2010].

Prophylaxis against sexually-transmitted diseases following sexual assault

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, metronidazole, in combination with ceftriaxone and azithromycin, is an effective and recommended regimen for prophylaxis against sexually transmitted diseases following sexual assault.

Skin and soft tissue necrotizing infections

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), metronidazole, in combination with cefotaxime or ceftriaxone, is an effective and recommended alternative for empiric treatment of mixed (polymicrobial) necrotizing infections of the skin, fascia, and muscle.

Surgical infection prophylaxis (preoperative)

Based on the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Surgical Infection Society (SIS), and the Society of Healthcare Epidemiology of America (SHEA) guidelines for antimicrobial prophylaxis in surgery, metronidazole is an effective and recommended agent (in combination with other antimicrobials) for appendectomy secondary to uncomplicated appendicitis, open biliary tract procedures, elective high risk laparoscopic biliary tract procedures, obstructed small intestine procedures, colorectal procedures (oral; IV is FDA-approved for this indication), clean-contaminated head and neck cancer surgery, other clean-contaminated procedures (except tonsillectomy and some endoscopic sinus procedures), hysterectomy (vaginal or abdominal), and clean-contaminated urologic procedures.

Surgical site infections

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), metronidazole, in combination with ceftriaxone, ciprofloxacin or levofloxacin, is an effective and recommended option for treatment of surgical site infections occurring after surgery of the intestinal or genitourinary tract, perineum, or axilla. Systemic antibacterials are not routinely indicated for surgical site infections, but may be beneficial (in conjunction with suture removal plus incision and drainage) in patients with significant systemic response (eg, temperature >38.5°C, heart rate >110 beats per minute, erythema/induration extending >5 cm from incision, WBC >12,000/mm3)..

Tetanus (adults)

Data from an open-label clinical trial in patients with moderate tetanus treated with either metronidazole or intramuscular procaine penicillin suggests that metronidazole may be beneficial and possibly superior to the use of penicillin for the treatment of this condition [Ahmadsyah 1985].

Tetanus (children)

Based on the American Academy of Pediatrics Report of the Committee on Infectious Disease, metronidazole is effective in decreasing the number of vegetative forms of C. tetani and is the recommended drug of choice for the treatment of children and adolescents with tetanus [AAP [Red Book 2012]].

Urethritis, nongonococcal (persistent and recurrent)

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, metronidazole is effective and recommended as treatment for recurrent and persistent urethritis for men who have sex with women and who live in areas where T. vaginalis is prevalent. Compliance with initial regimen and lack of re-exposure to an untreated sex partner should be excluded prior to use. Sex partners should be referred for evaluation and appropriate treatment.

Contraindications

Hypersensitivity to metronidazole, nitroimidazole derivatives, or any component of the formulation; pregnant patients (first trimester) with trichomoniasis; use of disulfiram within the past 2 weeks; use of alcohol or propylene glycol-containing products during therapy or within 3 days of therapy discontinuation

Canadian labeling: Additional contraindications (not in the US labeling): Active neurological disorders; history of blood dyscrasia; hypothyroidism; hypoadrenalism

Dosing: Adult

Amebiasis (acute dysentery): Oral: Immediate-release tablets and capsules: 750 mg every 8 hours for 5 to 10 days

Amebic liver abscess: Oral:

Immediate-release tablets: 500 to 750 mg every 8 hours for 5 to 10 days

Capsules: 750 mg every 8 hours for 5 to 10 days

Bacterial vaginosis or vaginitis due to Gardnerella, Mobiluncus: Oral: Tablet:

Immediate release (off-label use): 500 mg twice daily for 7 days (CDC [Workowski 2015])

Extended release: 750 mg once daily for 7 days

Intra-abdominal infection:

Manufacturer’s labeling: Oral (immediate release), IV: 500 mg every 6 hours (maximum: 4 g/day); Note: Initial: 1 g IV loading dose may be administered

Alternate dosing:

Acute diverticulitis, outpatient treatment: Oral (immediate release): 500 mg every 6 to 8 hours; use in combination with a fluoroquinolone (eg, ciprofloxacin) or sulfamethoxazole and trimethoprim (Jacobs 2007)

Complicated, community-acquired, mild to moderate (in combination with cephalosporin or fluoroquinolone): IV: 500 mg every 8 to 12 hours or 1.5 g every 24 hours for 4 to 7 days (provided source controlled) (Solomkin 2010)

Pelvic inflammatory disease (off-label dose): Oral (immediate release):

Mild to moderately severe: 500 mg twice daily for 14 days (may be added to a combination of a third-generation parenteral cephalosporin and doxycycline) (CDC [Workowski 2015])

With tubo-ovarian abscess: 500 mg twice daily to complete at least 14 days of therapy (in combination with doxycycline following a parenteral therapy regimen)

Trichomoniasis (index case and sex partner): Oral:

Immediate-release tablets:

Manufacturer’s labeling: 250 mg every 8 hours for 7 days or 1 g twice daily for 2 doses (on same day) or 2 g as a single dose

Alternate dosing: 2 g as a single dose (preferred regimen) or 500 mg twice daily for 7 days (off-label dose) (CDC [Workowski 2015])

Capsules: 375 mg twice daily for 7 days

Trichomoniasis in HIV-infected women (off-label dose): Oral (immediate release): 500 mg twice daily for 7 days (CDC [Workowski 2015])

Trichomoniasis, persistent or recurrent (ie, treatment failure of nitroimidazole [eg metronidazole] single-dose therapy) (index case; treatment of sex partner; off-label dose): Oral (immediate release): 500 mg twice daily for 7 days. If this regimen also fails, consider 2 g once daily for 7 days (CDC [Workowski 2015])

Balantidiasis (off-label use): IV, Oral (immediate release): 750 mg 3 times daily for ≥5 days (Anagyrou 2003; Schuster 2008)

Bite wounds (animal/human) (off-label use) (IDSA [Stevens 2014]): Note: Use in combination with a second- or third-generation cephalosporin, levofloxacin, or sulfamethoxazole/trimethoprim for animal bites, or in combination with ciprofloxacin or levofloxacin for human bites.

Oral: 250 to 500 mg 3 times daily

IV: 500 mg every 8 hours

Clostridium difficile infection (off-label use): Note: Avoid repeated or prolonged courses due to risk of cumulative and potentially irreversible neurotoxicity. In addition, criteria for disease severity is based on expert opinion and should not replace clinical judgment (IDSA/SHEA [McDonald 2018]).

Non-severe (supportive clinical data: WBC ≤15,000 cells/mm3 and serum creatinine <1.5 mg/dL), initial episode (alternative agent if oral vancomycin or fidaxomicin unavailable or contraindicated): Oral (immediate release): 500 mg 3 times daily for 10 days. Note: Treatment duration may be extended to 14 days if patient has improved but has not had symptom resolution (IDSA/SHEA [McDonald 2018]).

Fulminant infection (supportive clinical data: ileus, megacolon, and/or hypotension/shock): IV: 500 mg 3 times daily with oral and/or rectal vancomycin (IDSA/SHEA [McDonald 2018]; Surawicz 2013)

Crohn disease, management after surgical resection (off-label use): Oral (immediate release):

Monotherapy: 20 mg/kg/day (in 3 divided doses) for 3 months, beginning as soon as possible after surgery, immediately after refeeding (Rutgeerts 1995).

Combination therapy: 400 mg twice daily or 250 mg 3 times daily beginning as soon as oral intake is resumed after surgery (in combination with a thiopurine [azathioprine or mercaptopurine] or an anti-TNF [eg, adalimumab]) for 3 months (De Cruz 2015, D’Haens 2008).

Crohn disease, mild to moderate, treatment (off-label use): Oral (immediate release): 10 to 20 mg/kg/day (Lichtenstein 2009) or 500 mg twice daily (in combination with ciprofloxacin) (Steinhart 2002).

Dientamoeba fragilis infections (off-label use): Oral (immediate release): 500 to 750 mg 3 times daily for 10 days (CDC 2012)

Giardiasis (off-label use): Oral (immediate release): 250 to 500 mg 3 times daily for 5 to 10 days (Granados 2012)

Helicobacter pylori eradication (off-label use): Oral (immediate release):

American College of Gastroenterology guidelines (Chey 2007; Chey 2017):

Clarithromycin triple regimen: 500 mg 3 times daily in combination with clarithromycin 500 mg twice daily and a standard-dose or double-dose proton pump inhibitor twice daily; continue regimen for 14 days. Note: Avoid use of clarithromycin triple therapy in patients with risk factors for macrolide resistance (eg, prior macrolide exposure, local clarithromycin resistance rates ≥15%, eradication rates with clarithromycin-based regimens ≤85%) (ACG [Chey 2017]; Fallone 2016).

Bismuth quadruple regimen: 250 mg 4 times daily or 500 mg 3 or 4 times daily in combination with either bismuth subsalicylate 300 mg or bismuth subcitrate 120 to 300 mg 4 times daily, tetracycline 500 mg 4 times daily, and a standard-dose proton pump inhibitor twice daily; continue regimen for 10 to 14 days.

Concomitant regimen: 500 mg twice daily in combination with clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily, plus a standard-dose proton pump inhibitor twice daily; continue regimen for 10 to 14 days.

Sequential regimen: Amoxicillin 1 g twice daily plus a standard-dose proton pump inhibitor twice daily for 5 to 7 days; then follow with clarithromycin 500 mg twice daily, metronidazole 500 mg twice daily, and a standard-dose proton pump inhibitor twice daily for 5 to 7 days.

Hybrid regimen: Amoxicillin 1 g twice daily plus a standard-dose proton pump inhibitor twice daily for 7 days; then follow with amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, metronidazole 500 mg twice daily, and a standard-dose proton pump inhibitor twice daily for 7 days.

Periodontitis (associated with aggressive disease; off-label use): Oral (immediate release): 250 mg every 8 hours in combination with amoxicillin for 10 days; used in addition to scaling, root planing and pocket irrigation (Silva-Senem 2013)

Pouchitis (post ileal pouch-anal anastomosis, acute treatment; off-label use): Oral (immediate release): 400 to 500 mg three times daily for 7 days (Holubar 2010; Wall 2011)

Prophylaxis against sexually-transmitted diseases following sexual assault (off-label use): Oral (immediate release): 2 g as a single dose in combination with ceftriaxone and azithromycin (CDC [Workowski 2015])

Skin and soft tissue necrotizing infections (off-label use): IV: 500 mg every 6 hours, in combination with cefotaxime or ceftriaxone for empiric therapy of polymicrobial infections. Continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014]).

Surgical prophylaxis:

Manufacturer’s labeling: IV: 15 mg/kg 1 hour prior to surgical incision; followed by 7.5 mg/kg 6 and 12 hours after initial dose

Alternate dosing:

IV: 500 mg within 60 minutes prior to surgical incision in combination with other antibiotics (Bratzler 2013). Note: Considered a recommended agent for select procedures other than colorectal surgery (off-label use) (Bratzler 2013).

Oral (for colorectal surgical prophylaxis only; immediate release; off-label use): 1 g every 3 to 4 hours for 3 doses, starting after mechanical bowel preparation the afternoon and evening before the procedure with or without additional oral antibiotics and with an appropriate IV antibiotic prophylaxis regimen (Bratzler 2013).

Surgical site infections (intestinal or GU tract; axilla or perineum) (off-label use): IV: 500 mg every 8 hours; in combination with ceftriaxone, ciprofloxacin, or levofloxacin (IDSA [Stevens 2014]).

Tetanus (Clostridium tetani infection; off-label use): Oral (immediate release): 500 mg every 6 hours for 7 to 10 days in combination with supportive therapy (Ahmadsyah, 1985)

Urethritis, nongonococcal (recurrent or persistent urethritis in men who have sex with women and who live in regions where T. vaginalis is prevalent; off-label use): Oral (immediate release): 2 g as a single dose. Note: Compliance with initial regimen and lack of re-exposure to an untreated sex partner should be excluded prior to use (CDC [Workowski 2015])

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Some clinicians recommend using adjusted body weight in obese children. Dosing weight = IBW + 0.45 (TBW-IBW)

General dosing, susceptible infection (Red Book [AAP 2015]): Infants, Children, and Adolescents:

Oral: 30 to 50 mg/kg/day in divided doses 3 times daily; maximum daily dose: 2,250 mg/day

IV: 22.5 to 40 mg/kg/day in divided doses 3 times daily; maximum daily dose: 1,500 mg/day

Amebiasis: Infants, Children, and Adolescents: Oral: 35 to 50 mg/kg/day in divided doses every 8 hours for 7 to 10 days; maximum dose: 750 mg/dose; for severe infection or extraintestinal disease, IV may be necessary (Bradley 2017; Parasitic Infections 2013)

Appendicitis, perforated (divided dosing): Children and Adolescents: IV: 30 mg/kg/day in divided doses 3 times daily (Emil 2003)

Appendicitis, perforated (once-daily dosing): Limited data available: Children and Adolescents: IV: 30 mg/kg/dose once daily in combination with ceftriaxone; maximum reported daily dose: 1,500 mg/day (Yardeni 2013); however, other pediatric trials did not report a maximum; in adult patients, a maximum daily dose of 1,500 mg/day for once-daily dosing is suggested (IDSA [Solomokin 2010]); in pediatric patients, once-daily metronidazole in combination with ceftriaxone has been shown to have similar efficacy as triple-combination therapy with ampicillin, clindamycin, and gentamicin (Fraser 2010; St Peter 2006; St Peter 2008)

Balantidiasis (off-label use): Infants, Children, and Adolescents: Oral: 35 to 50 mg/kg/day in divided doses every 8 hours for 5 days; maximum dose: 750 mg/dose (Red Book [AAP 2015])

Catheter (peritoneal dialysis); exit-site or tunnel infection: Infants, Children, and Adolescents: Oral: 10 mg/kg/dose 3 times daily. Maximum dose: 500 mg/dose (ISPD [Warady 2012])

Clostridium difficile-associated diarrhea (CDAD; off-label use): Infants, Children, and Adolescents: Oral: 30 mg/kg/day divided every 6 hours for ≥10 days (maximum: 2,000 mg/day) (Red Book [AAP 2015]; AAP [Schutze 2013]).

Dientamoeba fragilis (off-label use): Infants, Children, and Adolescents: Oral: 35 to 50 mg/kg/day in divided doses every 8 hours for 10 days; maximum dose: 750 mg/dose (Red Book [AAP 2015])

Giardiasis (off-label use): Infants, Children, and Adolescents: Oral: 15 to 30 mg/kg/day in divided doses every 8 hours for 5 to 7 days; maximum dose: 250 mg/dose (Bradley 2017; Gardner 2001; Granados 2012; Ross 2013)

Helicobacter pylori eradication (off-label use): Children and Adolescents: Oral: 20 mg/kg/day in 2 divided doses for 10 to 14 days in combination with amoxicillin and a proton pump inhibitor with or without clarithromycin (maximum: 1,000 mg/day) (NASPGHAN/ESPGHAN [Koletzko 2011])

Inflammatory bowel disease (off-label use):

Crohn disease, perianal disease; induction: Children and Adolescents: Oral: 7.5 mg/kg/dose 3 times daily for 6 weeks with or without ciprofloxacin; maximum dose: 500 mg/dose (Sandhu 2010)

Ulcerative colitis, pouchitis, persistent: Children and Adolescents: Oral: 20 to 30 mg/kg/day in divided doses 3 times daily for 14 days with or without ciprofloxacin or oral budesonide; maximum dose: 500 mg/dose (Turner 2012)

Intra-abdominal infection: Infants, Children, and Adolescents: IV: 30 to 40 mg/kg/day in divided doses 3 times daily as part of combination therapy; maximum dose: 500 mg/dose (IDSA [Solomkin] 2010)

Pelvic inflammatory disease: Adolescents: Oral: 500 mg twice daily for 14 days; administer with doxycycline plus a cephalosporin (CDC [Workowski 2015])

Peritonitis (peritoneal dialysis) (ISPD [Warady 2012]):

Prophylaxis: Gastrointestinal or genitourinary procedures: Infants, Children, and Adolescents: IV: 10 mg/kg once prior to procedure in combination with cefazolin; Maximum dose: 1,000 mg/dose

Treatment: Infants, Children, and Adolescents: Oral: 10 mg/kg/dose 3 times daily. Maximum daily dose: 1,200 mg/day

Prophylaxis against sexually transmitted diseases following sexual assault (off-label use): Adolescents: Oral: 2,000 mg as a single dose in combination with azithromycin and ceftriaxone (CDC [Workowski 2015])

Surgical prophylaxis (off-label use): Children and Adolescents: IV: 15 mg/kg as a single dose 30 to 60 minutes prior to procedure; maximum single dose: 500 mg (IDSA/AHSP [Bratzler 2013])

Surgical prophylaxis, colorectal: Children and Adolescents: Oral: 15 mg/kg/dose every 3 to 4 hours for 3 doses, starting after mechanical bowel preparation the afternoon and evening before the procedure, with or without additional oral antibiotics and with an appropriate IV antibiotic prophylaxis regimen; maximum dose: 1,000 mg/dose (IDSA/ASHP [Bratzler] 2013)

Tetanus (Clostridium tetani infection; off-label use): Infants, Children, and Adolescents: Oral, IV: 30 mg/kg/day in divided doses every 6 hours for 7 to 10 days (maximum: 4,000 mg/day) (Red Book [AAP 2015])

Trichomoniasis, treatment: Oral:

Children <45 kg: 45 mg/kg/day in divided doses 3 times daily for 7 days; maximum daily dose: 2,000 mg/day (Red Book [AAP 2015])

Children ≥45 kg and Adolescents: 2,000 mg as a single dose once or 500 mg twice daily for 7 days (CDC [Workowski 2015]; Red Book [AAP 2015])

Vaginosis, bacterial: Children >45 kg and Adolescents: Oral: 500 mg twice daily for 7 days (CDC [Workowski 2015]; Red Book [AAP 2015])

Dosing: Renal Impairment

Manufacturer’s labeling:

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, decreased renal function does not alter the single-dose pharmacokinetics.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling; metronidazole metabolites may accumulate; monitor for adverse events.

ESRD requiring dialysis: Metronidazole metabolites may accumulate; monitor for adverse events. Accumulated metabolites may be rapidly removed by dialysis:

Intermittent hemodialysis (IHD): If administration cannot be separated from hemodialysis, consider supplemental dose following hemodialysis.

Peritoneal dialysis (PD): No dosage adjustment necessary.

Alternate dosing:

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Dialyzable (50% to 100%): 500 mg every 8 to 12 hours. Note: Dosing regimen highly dependent on clinical indication (trichomoniasis vs C. difficile colitis) (Heintz 2009). Note: Dosing dependent on the assumption of thrice weekly, complete IHD sessions.

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH/CVVHD/CVVHDF: 500 mg every 6 to 12 hours (or per clinical indication; dosage reduction generally not necessary)

Dosing: Hepatic Impairment

Manufacturer’s labeling:

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary; use with caution and monitor for adverse events

Severe impairment (Child-Pugh class C):

Extended-release tablets: Use is not recommended.

Immediate-release capsules:

Amebiasis: 375 mg 3 times daily

Trichomoniasis: 375 mg once daily

Immediate-release tablets, injection: Reduce dose by 50%

Alternate dosing: The pharmacokinetics of a single oral 500 mg dose were not altered in patients with cirrhosis; initial dose reduction is therefore not necessary (Daneshmend, 1982). In one study of IV metronidazole, patients with alcoholic liver disease (with or without cirrhosis), demonstrated a prolonged elimination half-life (eg, ~18 hours). The authors recommended the dose be reduced accordingly (clearance was reduced by ~62%) and the frequency may be prolonged (eg, every 12 hours instead of every 6 hours) (Lau, 1987). In another single IV dose study using metronidazole metabolism to predict hepatic function, patients classified as Child-Pugh class C demonstrated a half-life of ~21.5 hours (Muscara, 1995).

Extemporaneously Prepared

Note: A metronidazole suspension (50 mg/mL or 100 mg/mL) is commercially available as a compounding kit.

50 mg/mL Oral Suspension (ASHP Standard Concentration) (ASHP 2017)

A 50 mg/mL oral suspension may be made with tablets and a 1:1 mixture of Ora-Sweet and Ora-Plus. Crush twenty-four 250 mg tablets in a mortar and reduce to a fine powder. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental portions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well". Stable for 60 days at room temperature or refrigerated (Allen 1996).

Allen LV Jr, Erickson MA 3rd. Stability of ketoconazole, metolazone, metronidazole, procainamide hydrochloride, and spironolactone in extemporaneously compounded oral liquids. Am J Health Syst Pharm. 1996;53(17):2073-2078.8870895

Administration

IV: Infuse intravenously over 30 to 60 minutes. Avoid contact of drug solution with equipment containing aluminum.

Oral: Immediate-release tablets and capsules may be administered with food to minimize stomach upset. Extended-release tablets should be administered on an empty stomach (1 hour before or 2 hours after meals); do not split, crush, or chew.

Dietary Considerations

Immediate-release tablets and capsules may be administered with food to minimize stomach upset. Extended-release tablets should be taken on an empty stomach (1 hour before or 2 hours after meals).

Sodium: Injectable dosage form may contain sodium.

Ethanol: Use of ethanol is contraindicated during therapy and for 3 days after therapy discontinuation.

Storage

Oral:

Extended release: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Immediate release: Store at 15°C to 25°C (59°F to 77°F). Protect the tablets from light.

Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Avoid excessive heat. Do not refrigerate. Do not remove unit from overwrap until ready for use. Discard unused solution.

Drug Interactions

Alcohol (Ethyl): MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Alcohol (Ethyl). A disulfiram-like reaction may occur. Avoid combination

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Busulfan: MetroNIDAZOLE (Systemic) may increase the serum concentration of Busulfan. Management: The toxic effects of busulfan may be greatly increased with concomitant use of metronidazole. This combination should probably be avoided when possible. If these agents must be used together, increased monitoring for busulfan toxicity is recommended. Consider therapy modification

Capecitabine: MetroNIDAZOLE (Systemic) may increase serum concentrations of the active metabolite(s) of Capecitabine. Monitor therapy

Carbocisteine: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Carbocisteine. Specifically, metronidazole may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Avoid combination

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Avoid combination

Disulfiram: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). In particular, the risk for CNS toxicities such as psychosis may be increased. Avoid combination

Dronabinol: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Dronabinol. Specifically, metronidazole may produce severe intolerance to the alcohol contained in the dronabinol oral solution. Consider therapy modification

Floxuridine: MetroNIDAZOLE (Systemic) may increase serum concentrations of the active metabolite(s) of Floxuridine. Specifically, serum concentrations of fluorouracil may be increased. Monitor therapy

Fluorouracil (Systemic): MetroNIDAZOLE (Systemic) may increase the serum concentration of Fluorouracil (Systemic). Monitor therapy

Fosphenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Fosphenytoin. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Lithium: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Lithium. MetroNIDAZOLE (Systemic) may increase the serum concentration of Lithium. Monitor therapy

Lopinavir: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Lopinavir. Specifically, the combination of metronidazole and lopinavir/ritonavir solution, which contains 42% alcohol, may result in a disulfiram-like reaction. MetroNIDAZOLE (Systemic) may enhance the arrhythmogenic effect of Lopinavir. Management: Avoid the concomitant use of lopinavir/ritonavir and metronidazole if possible. If these agents are used concomitantly, monitor for QTc prolongation/arrhythmia and if the lopinavir/ritonavir solution is used, development of a disulfiram-like reaction. Consider therapy modification

Mebendazole: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Particularly the risk for Stevens-Johnson syndrome or toxic epidermal necrolysis may be increased. Avoid combination

Mycophenolate: MetroNIDAZOLE (Systemic) may decrease the serum concentration of Mycophenolate. Specifically, metronidazole may decrease concentrations of the active metabolite of mycophenolate. Monitor therapy

PHENobarbital: May decrease the serum concentration of MetroNIDAZOLE (Systemic). Monitor therapy

Phenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Phenytoin. Monitor therapy

Primidone: May decrease the serum concentration of MetroNIDAZOLE (Systemic). Monitor therapy

Products Containing Propylene Glycol: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Products Containing Propylene Glycol. A disulfiram-like reaction may occur. Avoid combination

Ritonavir: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Specifically, the combination of ritonavir oral solution or ritonavir soft gelatin capsule, both of which contain alcohol, and metronidazole may result in a disulfiram-like reaction. Avoid combination

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Tegafur: MetroNIDAZOLE (Systemic) may increase serum concentrations of the active metabolite(s) of Tegafur. Monitor therapy

Tipranavir: MetroNIDAZOLE (Systemic) may enhance the adverse/toxic effect of Tipranavir. A disulfiram-like reaction may occur due to the alcohol contained in tipranavir capsules. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vecuronium: MetroNIDAZOLE (Systemic) may enhance the neuromuscular-blocking effect of Vecuronium. Monitor therapy

Vitamin K Antagonists (eg, warfarin): MetroNIDAZOLE (Systemic) may increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding. Consider therapy modification

Test Interactions

May interfere with AST, ALT, triglycerides, glucose, and LDH testing

Adverse Reactions

>10%:

Central nervous system: Headache (18%)

Gastrointestinal: Nausea (10% to 12%)

Genitourinary: Vaginitis (15%)

1% to 10%:

Central nervous system: Metallic taste (9%), dizziness (4%)

Dermatologic: Genital pruritus (5%)

Gastrointestinal: Abdominal pain (4%), diarrhea (4%), xerostomia (2%)

Genitourinary: Dysmenorrhea (3%), urine abnormality (3%), urinary tract infection (2%)

Infection: Bacterial infection (7%), candidiasis (3%)

Respiratory: Flu-like symptoms (6%), upper respiratory tract infection (4%), pharyngitis (3%), sinusitis (3%)

Frequency not defined:

Cardiovascular: Chest pain, facial edema, flattened T-wave on ECG, flushing, palpitations, peripheral edema, syncope, tachycardia

Central nervous system: Aseptic meningitis, ataxia, brain disease, chills, confusion, convulsions, depression, disulfiram-like reaction (with alcohol), drowsiness, dysarthria, hypoesthesia, insomnia, irritability, malaise, numbness, paresthesia, peripheral neuropathy, psychosis, seizure, vertigo

Dermatologic: Erythematous rash, hyperhidrosis, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Decreased libido

Gastrointestinal: Abdominal cramps, abdominal distress, anorexia, constipation, decreased appetite, dysgeusia, glossitis, hairy tongue, pancreatitis (rare), proctitis, stomatitis, vomiting

Genitourinary: Cystitis, dark urine (rare), dyspareunia, dysuria, urinary incontinence, urine discoloration, vaginal dryness, vulvovaginal candidiasis

Hematologic & oncologic: Agranulocytosis, eosinophilia, leukopenia, neutropenia (reversible), thrombocytopenia (reversible, rare)

Hepatic: Increased liver enzymes, jaundice, severe hepatotoxicity (patients with Cockayne syndrome)

Hypersensitivity: Anaphylaxis, hypersensitivity

Immunologic: DRESS syndrome, serum sickness-like reaction (joint pains)

Local: Inflammation at injection site (IV), injection site reaction

Neuromuscular & skeletal: Arthralgia, muscle spasm, myalgia, weakness

Ophthalmic: Abnormal eye movements (saccadic), nystagmus, optic neuropathy

Renal: Polyuria

Respiratory: Dyspnea, nasal congestion, rhinitis

Miscellaneous: Fever, lesion (central nervous system, reversible)

ALERT: U.S. Boxed Warning

Carcinogenic:

Metronidazole has been shown to be carcinogenic in mice and rats. Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions for which this drug is indicated.

Warnings/Precautions

Concerns related to adverse effects:

• Carcinogenic: [US Boxed Warning]: Possibly carcinogenic based on animal data. Reserve use for conditions described in Use; unnecessary use should be avoided.

• CNS effects: Severe neurological disturbances, including aseptic meningitis (may occur within hours of a dose), cerebellar symptoms (ataxia, dizziness, dysarthria, nystagmus, saccadic pursuit), convulsive seizures, encephalopathy, optic neuropathy, and peripheral neuropathy (usually symmetric and of sensory type) have been reported. Encephalopathy is associated with widespread lesions on brain MRI; cerebellar toxicity is accompanied by T2 flair lesions within the dentate nuclei seen on MRI. Cerebellar toxicity may occur concurrently with encephalopathy, peripheral neuropathy, or seizures. CNS symptoms and CNS lesions are generally reversible within days to weeks of discontinuation of therapy; peripheral neuropathy symptoms may be prolonged after discontinuation. Monitor for neurologic symptoms and discontinue therapy if any abnormal neurologic symptoms occur.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Candidiasis infection (known or unknown) may be more prominent during metronidazole treatment, antifungal treatment required.

Disease-related concerns:

• Blood dyscrasias: Use with caution in patients with or history of blood dyscrasias; agranulocytosis, leukopenia, and neutropenia have occurred. Monitor CBC with differential at baseline, during and after treatment.

• Cockayne syndrome: Severe hepatotoxicity/acute hepatic failure (has been fatal) has been reported with systemic metronidazole in patients with Cockayne syndrome; onset is rapid after initiation of treatment. Use metronidazole only after risk vs benefit assessment and if there are no appropriate alternatives in patients with Cockayne syndrome. Obtain LFTs prior to treatment initiation, within the first 2 to 3 days of initiation, frequently during therapy, and after treatment is complete. Discontinue treatment if elevated LFTs occur and monitor until LFTs return to baseline.

• Hepatic impairment: Use with caution in patients with hepatic impairment due to potential accumulation; dosage adjustment recommended in patients with severe hepatic impairment.

• Renal impairment: Use with caution in patients with severe renal impairment or ESRD due to potential accumulation. Accumulated metabolites may be rapidly removed by hemodialysis; supplemental doses may be needed.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage-form specific issues:

• Extended-release tablets: Do not use in patients with severe hepatic impairment (Child-Pugh class C) unless benefit outweighs risk.

• Injection: Use injection with caution in patients with heart failure, edema, or other sodium-retaining states, including corticosteroid treatment due to high sodium content. In patients receiving continuous nasogastric secretion aspiration, sufficient metronidazole may be removed in the aspirate to cause a reduction in serum levels.

Other warnings/precautions:

• Ethanol use: Abdominal cramps, nausea, vomiting, headaches, and flushing have been reported with oral and injectable metronidazole and concomitant alcohol consumption (disulfiram-like reactions); avoid alcoholic beverages or products containing propylene glycol during oral or injectable therapy and for at least 3 days after therapy.

Monitoring Parameters

Monitor CBC with differential at baseline, during, and after prolonged or repeated courses of therapy. Monitor LFTs in patients with Cockayne syndrome. Closely monitor elderly patients and patients with severe hepatic impairment or ESRD for adverse reactions. Observe patients carefully if neurologic symptoms occur and consider discontinuation of therapy.

Pregnancy Considerations

Metronidazole crosses the placenta. Cleft lip with or without cleft palate has been reported following first trimester exposure to metronidazole; however, most studies have not shown an increased risk of congenital anomalies or other adverse events to the fetus following maternal use during pregnancy. Because metronidazole was carcinogenic in some animal species, concern has been raised whether metronidazole should be used during pregnancy. Available studies have not shown an increased risk of infant cancer following metronidazole exposure during pregnancy; however, the ability to detect a signal for this may have been limited.

Metronidazole pharmacokinetics are similar between pregnant and nonpregnant patients (Amon 1981; Visser 1984; Wang 2011).

Bacterial vaginosis and vaginal trichomoniasis are associated with adverse pregnancy outcomes and metronidazole is recommended for the treatment of symptomatic pregnant patients. The dose of oral metronidazole for the treatment of bacterial vaginosis during pregnancy is the same as the CDC recommended twice daily dose in nonpregnant females. When treating vaginal trichomonisais, the CDC recommends the single oral dose regimen in pregnancy. Although use of metronidazole for vaginal trichomoniasis during the first trimester is contraindicated by the manufacturer; available guidelines note treatment can be given at any stage of pregnancy (Workowski [CDC 2015]).

Metronidazole may also be used for the treatment of giardiasis in pregnant women (some sources recommend second and third trimester administration only) (Gardner 2001; HHS [OI adult 2017]) and symptomatic amebiasis during pregnancy (HHS [OI adult 2017]; Li 1996). Short courses may be used for the treatment of pouchitis or perianal disease in pregnant women with inflammatory bowel disease (avoid use in the first trimester) (van der Woude 2015).The use of other agents is preferred when treatment is needed during pregnancy for Clostridium difficile (Surawicz 2013). Consult current recommendations for appropriate use in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, constipation, lack of appetite, abdominal cramps, abdominal pain, fatigue, muscle pain, joint pain, muscle spasm, decreased libido, injection site irritation, or metallic taste. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), involuntary eye movements, angina, tachycardia, abnormal heartbeat, shortness of breath, bruising, bleeding, swelling of arms or legs, signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), change in balance, dizziness, passing out, headache, difficulty speaking, seizures, thrush, vaginitis, vision changes, irritability, depression, confusion, loss of strength or energy, insomnia, burning or numbness feeling, or signs of aseptic meningitis (headache, fever, chills, severe nausea or vomiting, stiff neck, rash, sensitivity to lights, fatigue, or confusion) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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